Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome, June 8, 2011, Bonadona et al. 305 (22): 2304 — JAMA

Original Contribution

JAMA. 2011;305(22):2304-2310. doi: 10.1001/jama.2011.743 Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome Valérie Bonadona, MD, PhD; Bernard Bonaïti, MSc; Sylviane Olschwang, MD, PhD; Sophie Grandjouan, MD; Laetitia Huiart, MD; Michel Longy, MD, PhD; Rosine Guimbaud, MD; Bruno Buecher, MD, PhD; Yves-Jean Bignon, MD, PhD; Olivier Caron, MD; Chrystelle Colas, MD; Catherine Noguès, MD; Sophie Lejeune-Dumoulin, MD; Laurence Olivier-Faivre, MD, PhD; Florence Polycarpe-Osaer, MD; Tan Dat Nguyen, MD; Françoise Desseigne, MD; Jean-Christophe Saurin, MD, PhD; Pascaline Berthet, MD; Dominique Leroux, MD, PhD; Jacqueline Duffour, MD; Sylvie Manouvrier, MD, PhD; Thierry Frébourg, MD, PhD; Hagay Sobol, MD, PhD; Christine Lasset, MD, PhD; Catherine Bonaïti-Pellié, MD, PhD for the French Cancer Genetics Network

[+] Author Affiliations

Author Affiliations: Université Lyon 1, Centre National de la Recherche Scientifique (CNRS) UMR 5558, Villeurbanne (Drs Bonadona and Lasset); Centre Léon Bérard, Lyon (Drs Bonadona, Desseigne, and Lasset); Institut National de la Sante et de la Recherche Medicale (INSERM), U669, Villejuif (Mr Bonaïti and Dr Bonaïti-Pellié); Institut National de la Recherche Agronomique (INRA)–GABI, Jouy-en-Josas (Mr Bonaïti); Institut Paoli-Calmettes, Marseille (Drs Olschwang, Huiart, and Sobol); INSERM, U891, Marseille (Dr Olschwang and Sobol); Assistance Publique-Hopitaux de Paris (APHP) Cochin, Paris (Dr Grandjouan); INSERM UMR 912, Marseille (Dr Huiart); Institut Bergonié, Bordeaux (Dr Longy); Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU) Toulouse (Dr Guimbaud), Toulouse; CHU, Nantes (Dr Buecher); Centre Jean Perrin, Clermont-Ferrand (Dr Bignon); Institut Gustave Roussy, Villejuif (Dr Caron); APHP Groupe Hospitalier de la Pitié-Salpétrière, INSERM UMRS 938, and Université Pierre et Marie Curie (Dr Colas), Paris; Institut Curie, Hôpital René Huguenin, Saint-Cloud (Dr Noguès); Centre Hospitalier Régional Universitaire (CHRU), and Université Lille 2 (Drs Lejeune-Dumoulin and Manouvrier), Lille; Hôpital d’Enfants, Dijon (Dr Olivier-Faivre); Centre Paul Strauss, Strasbourg (Dr Polycarpe-Osaer); Institut Jean Godinot, Reims (Dr Nguyen); Hopital Edouard Herriot, Lyon (Dr Saurin); Centre François Baclesse, Caen (Dr Berthet); CHU de Grenoble, Grenoble (Dr Leroux); Centre Val d’Aurelle, Montpellier (Dr Dufour); INSERM, U614, Rouen; and CHU, Rouen (Dr Frébourg); Université de la Méditerranée, Aix-Marseille II, Marseille (Dr Sobol); and Université Paris-Sud, Villejuif (Dr Bonaïti-Pellié), France. Other members of the French Cancer Genetics Network who participated in this study are listed in the Appendix.


Abstract
Context Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome.

Objective To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes.

Design, Setting, and Participants Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed.

Main Outcome Measure Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias.

Results Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations.

Conclusions MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.

Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome, June 8, 2011, Bonadona et al. 305 (22): 2304 — JAMA